BV-CHEP Chemotherapy for Adult T-cell Leukemia or Lymphoma

STUDY OBJECTIVES

Primary Objective To define the proportion of subjects with CR after 4-6 cycles of
brentuximab vedotin in combination with cyclophosphamide, doxorubicin, etoposide, and
prednisone (BV-CHEP) in the treatment of adult T-cell leukemia/lymphoma.

Secondary Objectives

To estimate the overall response rate (ORR) with 4-6 cycles of BV-CHEP therapy in patients
with adult T-cell leukemia/lymphoma.

To determine progression-free survival (PFS) for BV-CHEP in patients with adult T-cell
leukemia/lymphoma who received or did not receive BV maintenance.

To determine duration of response to BV-CHEP in patients with adult T-cell leukemia/lymphoma
who received or did not receive BV maintenance.

To determine overall survival (OS) of patients with adult T-cell leukemia/lymphoma treated
with BV-CHEP who received or did not receive BV maintenance therapy.

To evaluate the toxicity and tolerability of BV-CHEP and BV maintenance therapy via the
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03).

*Note: After completion or withdrawal from BV-CHEP therapy, patients will segregate into one
of the following groups: 1) those who progressed on BV-CHEP; 2) those who completed 4-6
cycles of BV-CHEP and went on to allogeneic transplant; 3) those who completed 6 cycles of
BV-CHEP but were CD30 negative and ineligible for maintenance therapy; and 4) those who
completed 6 cycles of BV-CHEP, were CD30 positive, but continued study treatment on BV in the
maintenance phase of the study.

ENDPOINTS

Primary Endpoint

Criteria for CR after 4-6 cycles of BV-CHEP will be based on the International Workshop to
standardize response criteria for malignant lymphomas (ie, Lugano Criteria per Cheson, et al.
J Clin Oncol. 2014;32(27):3059-68).

Secondary Endpoints

Criteria for overall response will be based on the International Workshop to standardize
response criteria for malignant lymphomas (ie, Lugano Criteria per Cheson, et al. J Clin
Oncol. 2014;32(27):3059-68).

PFS is defined as time from D1 of treatment until disease progression (based on Lugano
criteria) or death from any cause.

Duration of response is defined as the time from documentation of tumor response per Lugano
criteria to disease progression

OS is defined as the time from D1 of treatment until death from any cause

Toxicity and tolerability of therapy will be assessed via the NCI CTCAE v4.03

TREATMENT INFORMATION

Patients will undergo screening to see if they are eligible. If eligible, participants will
start by receiving 2 cycles of BV-CHEP (cycles 1 and 2). After 2 cycles of BV-CHEP,
participants will have a positron emission tomography/computed tomography (PET/CT) or a CT
scan to assess their disease. If the scan shows the cancer has stayed the same or gotten
better, participants may continue taking BV-CHEP for two more cycles (cycle 3 and 4). If, at
any time during study treatment, a participant's disease gets worse, the participant will end
study treatment and other treatment options will be discussed with you.

If a participant continues on BV-CHEP, at the beginning of cycle 5, the participant will have
a PET/CT scan. If the cancer has gotten better and the participant is eligible for a bone
marrow transplant, he/she will have the transplant. If the participant is not eligible for a
bone marrow transplant and the cancer has stayed the same or gotten better, the participant
may continue on BV-CHEP for two more cycles (cycles 5 and 6).

At the end of cycle 6 of BV-CHEP, participants will have another PET/CT scan. If the scan
shows the cancer has gotten better and the participant is eligible for a bone marrow
transplant, he/she will have the transplant. If a participant is not eligible for a bone
marrow transplant and his/her cancer cells did not test positive for CD30, the participant
will end study treatment. The study doctor will discuss other treatment options that are not
part of this study with the participant.

Participants may continue on brentuximab vedotin alone as maintenance therapy if:

- They are not eligible for a bone marrow transplant,

- Their cancer cells tested positive for CD30, and

- Their cancer has not gotten worse after taking BV-CHEP.

Participants will be removed from BV maintenance therapy if their cancer get worse.

DURATION OF THERAPY Therapy in LCCC 1637 involves up to 6 cycles of treatment with
brentuximab vedotin (BV) with a chemotherapy treatment made up of cyclophosphamide,
doxorubicin, etoposide, and prednisone (CHEP). Each cycle is 21 days long. Participants may
continue on BV alone as maintenance therapy after 6 cycles of BV-CHEP if they meet the
requirements outlined above. Each cycles of BV maintenance therapy is 21-day long. BV
maintenance therapy may continue until a participant's disease progresses.

DURATION OF FOLLOW-UP PERIOD Participants will be followed for survival for up to 5 years.
They will also have a PET/CT or CT scan and a blood test every 6 months for 2 years after
study treatment ends.

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria to participate in this study:

1. Informed consent and HIPAA authorization for release of personal health information
obtained.

2. Age ≥ 18 years at the time of consent.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

4. Histological confirmation of biopsy-proven peripheral T-cell leukemia/lymphoma
consistent with ATLL

- Included subtypes will be: acute, lymphomatous, and chronic unfavorable. Chronic
unfavorable is defined as the chronic variant with at least one of the following:
lactate dehydrogenase (LDH)>upper limit of normal (ULN), blood urea nitrogen
(BUN)>ULN, Albumin
- Positive human T-lymphotropic virus-1 (HTLV-1) antibody testing with confirmatory
testing via Western blot, enzyme-linked immunosorbent assay (ELISA), or molecular
testing (PCR).

5. Documented negative serologic testing for human immunodeficiency virus (HIV).

6. If positive for HBV exposure or prior infection, can continue to participate in trial
with prophylactic entecavir (for HBV). If positive for hepatitis c virus (HCV)
exposure or active infection, can participate in trial with monitoring for liver
function abnormalities.

7. Demonstrate adequate organ function as defined below; all screening labs to be
obtained within three days prior to study treatment.

System: Renal -Calculated creatinine clearance

Laboratory Value: ≥ 30 mL/min using the Cockcroft-Gault formula for subjects with
creatinine levels > 2.0 x institutional ULN

System: Hepatic - Bilirubin

Laboratory Value: ≤ 3.0 mg/dL

System: Hepatic - Aspartate aminotransferase (AST)

Laboratory Value: ≤ 2.5 × ULN

System: Hepatic - Alanine aminotransferase (ALT)

Laboratory Value: ≤ 2.5 × ULN

8. Females of childbearing potential must have a negative serum pregnancy test within
three days (72 hours) prior to initiating study treatment. NOTE: Females are
considered of child bearing potential unless they are surgically sterile (have
undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they
are naturally postmenopausal for at least 12 consecutive months.

9. Females of childbearing potential must be willing to abstain from heterosexual
activity or to use 2 forms of effective methods of contraception from the time of
informed consent until 24 weeks (6 months) after treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method or an intrauterine device that meets <1% failure rate for
protection from pregnancy in the product label.

10. Male patients with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e., double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 24 weeks (6 months) after
the last dose of study therapy.

11. As determined by the enrolling physician or protocol designee, willingness and ability
of the subject to understand and comply with study procedures

12. Prior Treatment: Previously untreated or has received a maximum of one cycle of any
combination chemotherapy (e.g. cyclophosphamide, doxorubicin, vincristine, prednisone
(CHOP), CHOEP, DA-EPOCH, doxorubicin, cyclophosphamide, cytarabine, vincristine,
methotrexate/Etoposide, ifosfamide, cytarabine, methotrexate (CODOX-M/IVAC),
HyperCVAD) within 4 weeks of study entry (defined as when the subject signs the main
consent form). Additionally, a patient may have taken antiretroviral therapy (e.g.
azidothymidine (AZT) and/or IFN) at any time prior to study enrollment

Exclusion Criteria:

Subjects who meet any of the following criteria should be excluded from study
participation:

1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).

2. Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been
disease-free for at least five years.

3. Previous exposure to brentuximab vedotin (BV).

4. History of allergic response to BV-CHEP or its components or to any of the required
prophylactic medications or reasonable alternatives.

5. Symptomatic cardiac disease including ventricular dysfunction, left ventricular
ejection fraction < 40%, symptomatic coronary artery disease or symptomatic
arrhythmias

6. Subjects with severe hepatic insufficiency Child-Pugh Score > 6

7. Subjects with severe renal impairment (i.e., creatinine clearance ≤ 30 mL/min; see
Appendix B - Renal Impairment Guidelines).

8. Exclude patients with pre-existing neuropathy grade 2 or higher.

9. Patients receiving prohibited medications listed in the patient handout provided in
11.4 Appendix D: Prohibited Medications or Those to be used with Caution (ie,
ketoconazole, itraconazole, ritonavir, macrolide antibiotics, erythromycin phenytoin,
phenobarbital, carbamazepine, and valproic acid).

10. Patients with a parenchymal brain lesion thought to be consistent with active lymphoma
on screening CT/MRI. Of note, patients with cerebrospinal fluid (CSF) involvement
alone are not excluded.